Heteroaryl alkyl piperazine derivatives

Details Heteroaryl alkyl piperazine derivatives Heteroaryl alkyl piperazine derivatives

2000-10-23

2003-06-03

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253010, C514S253060, C514S254020, C514S254090, C544S354000, C544S360000, C544S363000, C544S368000, C544S373000

Reexamination Certificate

active

06573264

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is concerned with piperazine derivatives, therapeutic dosage forms including one or more of the derivatives, and methods for treating diseases in mammals, and in particular, in a human in a therapy selected from the group including protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
2. Description of the Art
U.S. Pat. No. 4,567,264, the specification of which is incorporated herein by reference, discloses a class of substituted piperazine compounds that includes a compound known as ranolazine, (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise-induced angina, and myocardial infarction.
U.S. Pat. No. 5,506,229, which is incorporated herein by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants. In particular, ranolazine is particularly useful for treating arrhythmias, variant and exercise-induced angina, and myocardial infarction by partially inhibiting cardiac fatty acid oxidation. Conventional oral and parenteral ranolazine formulations are disclosed, including controlled release formulations. In particular, Example 7D of U.S. Pat. No. 5,506,229 describes a controlled release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.
Despite the important discovery that ranolazine is a very useful cardiac therapeutic agent, there remains a need for compounds that are partial fatty acid oxidation inhibitors that have a half-life greater than ranolazine and that have activities as least similar to ranolazine.
SUMMARY OF THE INVENTION
This invention includes novel heteroaryl alkyl piperazine derivatives that are partial fatty acid oxidation inhibitors with good therapeutic half-lives.
This invention also includes novel substituted piperazine compounds that can be administered to a mammal to protect skeletal muscles against damage resulting from trauma, to protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
This invention includes a class of substituted piperazine compounds having the formula:
wherein m=1, 2, or 3;
q=NH, O, or S;
R
1
, R
2
, R
3
, R
4
and R
5
are each independently selected from the group consisting of hydrogen, halo, NO
2
, CF
3
, CN, OR
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, NR
20
CO
2
R
22
, NR
20
CON(R
20
)
2
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, NR
20
SO
2
R
22
, C
1-15
alkyl, C
2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO
2
, CF
3
, CN, OR
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, and SO
2
R
22
;
R
6
, R
7
and R
8
each independently selected from the group consisting of hydrogen or C
1-3
alkyl;
R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
and R
16
are each independently selected from the group consisting of hydrogen, CO
2
R
20
, CON(R
20
)
2
, C
1-4
alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF
3
, CN, OR
20
, N(R
20
)
2
, CO
2
R
20
, CON(R
20
)
2
or aryl, wherein R
9
and R
10
may together form a carbonyl, or R
11
and R
12
may together form a carbonyl, or R
13
and R
14
may together form a carbonyl, or R
15
and R
16
may together form a carbonyl or R
11
and R
13
or R
9
and R
15
or R
9
and R
11
or R
11
and R
15
or R
9
and R
13
may join together to form a ring including from 1 to 3 carbon atoms;
R
17
is heteroaryl that is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO
2
, CF
3
, CN, OR
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, SO
2
R
22
, SO
2
N(R
20
)
2
, NR
20
CO
2
R
22
, NR
20
CON(R
20
)
2
, COR
20
, CO
2
R
20
, CON(R
20
)
2
, NR
20
SO
2
R
22
, C
1-15
alkyl, C
2-15
alkenyl, C
2-15
alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO
2
, CF
3
, CN, OR
20
, SR
20
, N(R
20
)
2
, S(O)R
22
, or SO
2
R
22
;
R
20
is selected from the group consisting of H, C
1-15
alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl CN, —O—C
1-6
alkyl, or CF
3
; and
R
22
is selected from the group consisting of C
1-15
alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O—C
1-6
alkyl, CF
3
, or heteroaryl.
In another embodiment, this invention is a substituted piperazine compound selected from the group consisting of N-(2,6-dimethyl-phenyl)-2-(4-{2-hydroxy-3-[2-(3-trifluoromethylphenyl)-benzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide, 2-{4-[3-(benzothiazol-2-yloxy)-2-hydroxy-propyl]-piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide,4-(3-{4-[(2,6-dimethylphenylcarbamoyl)-methyl]-piperazin-1-yl}-2-hydroxy-propoxy)-1H-indole-2-carboxylic acid amide, 2-{4-[3-(benzothiazol-6-yloxy)2-hydroxy-propyl]-piperazin-1-yl}-N-(2,6-dimethyl-phenyl)-acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-6-yloxy)-propyl]-piperazin-1-yl}aceamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-3,5-dimethyl-piperazine-1-yl}acetamide, 2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}-N-(4-hydroxy-phenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-phenyl-benzothiazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-phenyl-benzoxazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide, N-(2,6-dimethylphenyl)2-{4-[2-hydroxy-3-(2-phenyl-benzothiazol-7-yloxy)-propyl]-piperazin-1-ylacetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]-2-oxo-piperazin-1-yl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methyl-benzoxazol-5-yloxy)-propyl]-piperazin-1-yl}acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[2-(4-trifluoromethyl-phenyl)-benzoxazol-5-yloxy]-propyl}-piperazin-1-yl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(quinoxalin-2-yloxy)-propyl]-piperazin-1-yl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(pyridin-3-yloxy)-propyl]-piperazin-1-yl

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